Physiological vibration detection in an implanted medical device

ABSTRACT

An embodiment of an implantable system configured to be implanted in a patient includes an accelerometer, a neural stimulator, and a controller. The neural stimulator is configured to deliver neural stimulation to a neural target. The controller is configured to use the accelerometer to detect laryngeal vibration or coughing, and is configured to deliver a programmed neural stimulation therapy using the neural stimulator and using detected laryngeal vibration or detected coughing as an input to the programmed neural stimulation therapy.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/225,832, filed on Jul. 15, 2009, under 35 U.S.C. §119(e), which ishereby incorporated by reference in its entirety.

TECHNICAL FIELD

This application relates generally to medical devices and, moreparticularly, to systems, devices and methods for sensing laryngealvibration or cough.

BACKGROUND

Implanting a chronic electrical stimulator, such as a cardiacstimulator, to deliver medical therapy(ies) is known. Examples ofcardiac stimulators include implantable cardiac rhythm management (CRM)devices such as pacemakers, implantable cardiac defibrillators (ICDs),and implantable devices capable of performing pacing and defibrillatingfunctions.

CRM devices are implantable devices that provide electrical stimulationto selected chambers of the heart in order to treat disorders of cardiacrhythm. An implantable pacemaker, for example, is a CRM device thatpaces the heart with timed pacing pulses. If functioning properly, thepacemaker makes up for the heart's inability to pace itself at anappropriate rhythm in order to meet metabolic demand by enforcing aminimum heart rate. Some CRM devices synchronize pacing pulses deliveredto different areas of the heart in order to coordinate the contractions.Coordinated contractions allow the heart to pump efficiently whileproviding sufficient cardiac output.

It has been proposed to stimulate neural targets (referred to as neuralstimulation, neurostimulation or neuromodulation) to treat a variety ofpathological conditions. For example, research has indicated thatelectrical stimulation of the carotid sinus nerve can result inreduction of experimental hypertension, and that direct electricalstimulation to the pressoreceptive regions of the carotid sinus itselfbrings about reflex reduction in experimental hypertension.

SUMMARY

Various embodiments discussed herein relate to the detection oflaryngeal vibration and coughing.

An embodiment of an implantable system configured to be implanted in apatient includes an accelerometer, a neural stimulator, and acontroller. The neural stimulator is configured to deliver neuralstimulation to a neural target. The controller is configured to use theaccelerometer to detect laryngeal vibration or coughing, and isconfigured to deliver a programmed neural stimulation therapy using theneural stimulator and using detected laryngeal vibration or detectedcoughing as an input to the programmed neural stimulation therapy.

According to a method embodiment, an accelerometer is used to detectlaryngeal vibration or coughing. A neural stimulation therapy iscontrolled using detected laryngeal vibration or detected coughing as aninput to the neural stimulation therapy.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Thescope of the present invention is defined by the appended claims andtheir equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments are illustrated by way of example in the figures ofthe accompanying drawings. Such embodiments are demonstrative and notintended to be exhaustive or exclusive embodiments of the presentsubject matter.

FIG. 1 illustrates various technologies for sensing physiologic signalsused in various embodiments of the present subject matter.

FIG. 2 illustrates an implantable neural stimulator and an implantableCRM device, according to various embodiments.

FIG. 3 illustrates heart sounds S1 and S2, such as may be detected usingan accelerometer.

FIG. 4 illustrates a relationship between heart sounds and both the QRSwave and left ventricular pressure.

FIG. 5 illustrates an embodiment of a method for calculating an intervalbetween heart sounds, used to determine heart rate.

FIG. 6 illustrates an embodiment of a method for using heart sounds tocalculate an average rate or to calculate HRV.

FIG. 7 illustrates an embodiment of a method for using heart sounds todetermine heart rate during time periods with neural stimulation andtime periods without neural stimulation.

FIG. 8 illustrates an embodiment of a method for using heart sounds todetect arrhythmia.

FIG. 9 illustrates an embodiment of a method for modulating neuralstimulation based on heart rate determined using heart sounds.

FIG. 10 illustrates an embodiment of a combined neural lead withdedicated neural stimulation electrodes and cardiac electrogram sensingelectrodes (unipolar to can or bipolar).

FIG. 11 illustrates an embodiment of an implantable neural stimulationdevice with a neural stimulation lead and a separate sensing stub leadused to remotely detect cardiac activity.

FIGS. 12A-12B illustrate an embodiment of a device with narrow fieldvector sensing capabilities.

FIG. 13 illustrates an embodiment of a device with wide field vectorsensing capabilities.

FIG. 14 illustrates remote cardiac R-wave detection for remote cardiacrate determination, according to various embodiments.

FIG. 15 illustrates an embodiment of a method for monitoring heart ratefor feedback to a neural stimulation therapy.

FIG. 16 illustrates an embodiment of a method for trending heart rateinformation for a neural stimulation therapy.

FIG. 17 illustrates an embodiment of a method for detecting arrhythmia.

FIG. 18 illustrates an embodiment of a method for modulating a neuralstimulation therapy.

FIG. 19 illustrates an embodiment of remote cardiac pace detectioncircuitry.

FIG. 20 illustrates a flow diagram of an embodiment for detecting pulsesusing the pace detection circuitry illustrated in FIG. 19.

FIG. 21 illustrates an embodiment of a method for correlating a detectedpace to a right ventricle pace.

FIG. 22 illustrates an embodiment of a method for detectingantitachycardia pacing (ATP).

FIG. 23 illustrates an embodiment of a method that uses antitachycardiapacing as an input to a neural stimulation therapy.

FIG. 24 illustrates various embodiments of closed loop neuralstimulation that use detected pacing as an input.

FIG. 25 illustrates an example of band-pass filtered tracheal sound,such as may be used in various embodiments.

FIG. 26 illustrates an embodiment of a method for filtering trachealsound.

FIG. 27 illustrates an embodiment of a method for titrating neuralstimulation.

FIG. 28 illustrates an embodiment of a method for detecting laryngealvibration by monitoring an accelerometer filtered to a neuralstimulation frequency.

FIG. 29 illustrates an embodiment of a method for controlling neuralstimulation.

FIG. 30 illustrates an embodiment of a method for controlling neuralstimulation using a filtered accelerometer signal monitored over aneural stimulation burst.

FIG. 31 illustrates an embodiment of a method for rapidly titratingneural stimulation therapy using accelerometer data.

FIG. 32 illustrates an embodiment of a method for using an accelerometerto remotely sense respiratory parameter(s) for diagnostic purposes orfor a closed loop neural stimulation.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

Physiology Overview

Provided herein, for the benefit of the reader, is a brief discussion ofphysiology related to autonomic neural stimulation. The autonomicnervous system (ANS) regulates “involuntary” organs, while thecontraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.

The heart rate and force are increased when the sympathetic nervoussystem is stimulated, and is decreased when the sympathetic nervoussystem is inhibited (or the parasympathetic nervous system isstimulated). An afferent nerve conveys impulses toward a nerve center.An efferent nerve conveys impulses away from a nerve center.

Stimulating the sympathetic and parasympathetic nervous systems can haveeffects other than heart rate and blood pressure. For example,stimulating the sympathetic nervous system dilates the pupil, reducessaliva and mucus production, relaxes the bronchial muscle, reduces thesuccessive waves of involuntary contraction (peristalsis) of the stomachand the motility of the stomach, increases the conversion of glycogen toglucose by the liver, decreases urine secretion by the kidneys, andrelaxes the wall and closes the sphincter of the bladder. Stimulatingthe parasympathetic nervous system (inhibiting the sympathetic nervoussystem) constricts the pupil, increases saliva and mucus production,contracts the bronchial muscle, increases secretions and motility in thestomach and large intestine, increases digestion in the small intention,increases urine secretion, and contracts the wall and relaxes thesphincter of the bladder. The functions associated with the sympatheticand parasympathetic nervous systems are many and can be complexlyintegrated with each other.

Vagal modulation may be used to treat a variety of cardiovasculardisorders, including but not limited to heart failure, post-MI(myocardial infarction) remodeling, and hypertension. These conditionsare briefly described below.

Heart failure refers to a clinical syndrome in which cardiac functioncauses a below normal cardiac output that can fall below a leveladequate to meet the metabolic demand of tissues. Heart failure maypresent itself as congestive heart failure (CHF) due to the accompanyingvenous and pulmonary congestion. Heart failure can be due to a varietyof etiologies such as ischemic heart disease, hypertension and diabetes.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to heart failure. Hypertension generallyrelates to high blood pressure, such as a transitory or sustainedelevation of systemic arterial blood pressure to a level that is likelyto induce cardiovascular damage or other adverse consequences.Hypertension has been arbitrarily defined as a systolic blood pressureabove 140 mm Hg or a diastolic blood pressure above 90 mm Hg.Consequences of uncontrolled hypertension include, but are not limitedto, retinal vascular disease and stroke, left ventricular hypertrophyand failure, myocardial infarction, dissecting aneurysm, andrenovascular disease.

Cardiac remodeling refers to a complex remodeling process of theventricles that involves structural, biochemical, neurohormonal, andelectrophysiologic factors, which can result following an MI or othercause of decreased cardiac output. Ventricular remodeling is triggeredby a physiological compensatory mechanism that acts to increase cardiacoutput due to so-called backward failure which increases the diastolicfilling pressure of the ventricles and thereby increases the so-calledpreload (i.e., the degree to which the ventricles are stretched by thevolume of blood in the ventricles at the end of diastole). An increasein preload causes an increase in stroke volume during systole, aphenomena known as the Frank-Starling principle. When the ventricles arestretched due to the increased preload over a period of time, however,the ventricles become dilated. The enlargement of the ventricular volumecauses increased ventricular wall stress at a given systolic pressure.Along with the increased pressure-volume work done by the ventricle,this acts as a stimulus for hypertrophy of the ventricular myocardium.The disadvantage of dilatation is the extra workload imposed on normal,residual myocardium and the increase in wall tension (Laplace's Law)which represent the stimulus for hypertrophy. If hypertrophy is notadequate to match increased tension, a vicious cycle ensues which causesfurther and progressive dilatation. As the heart begins to dilate,afferent baroreceptor and cardiopulmonary receptor signals are sent tothe vasomotor central nervous system control center, which responds withhormonal secretion and sympathetic discharge. The combination ofhemodynamics, sympathetic nervous system and hormonal alterations (suchas presence or absence of angiotensin converting enzyme (ACE) activity)accounts for the deleterious alterations in cell structure involved inventricular remodeling. The sustained stresses causing hypertrophyinduce apoptosis (i.e., programmed cell death) of cardiac muscle cellsand eventual wall thinning which causes further deterioration in cardiacfunction. Thus, although ventricular dilation and hypertrophy may atfirst be compensatory and increase cardiac output, the processesultimately result in both systolic and diastolic dysfunction. It hasbeen shown that the extent of ventricular remodeling is positivelycorrelated with increased mortality in post-MI and heart failurepatients.

Therapy Examples

Various embodiments provide a stand-alone device, either externally orinternally, to provide neural stimulation therapy. For example, thepresent subject matter may deliver anti-remodeling therapy throughneural stimulation as part of a post-MI or heart failure therapy. Neuralstimulation may also be used in a hypertension therapy and conditioningtherapy, by way of example and not limitation. The present subjectmatter may also be implemented in non-cardiac applications, such as intherapies to treat epilepsy, depression, pain, obesity, hypertension,sleep disorders, and neuropsychiatric disorders. Various embodimentsprovide systems or devices that integrate neural stimulation with one ormore other therapies, such as bradycardia pacing, anti-tachycardiatherapy, remodeling therapy, and the like.

Neural Stimulation Therapies

Examples of neural stimulation therapies include neural stimulationtherapies for respiratory problems such a sleep disordered breathing,for blood pressure control such as to treat hypertension, for cardiacrhythm management, for myocardial infarction and ischemia, for heartfailure, for epilepsy, for depression, for pain, for migraines and foreating disorders and obesity. Many proposed neural stimulation therapiesinclude stimulation of the vagus nerve. This listing of other neuralstimulation therapies is not intended to be an exhaustive listing.Neural stimulation can be provided using electrical, acoustic,ultrasound, light, and magnetic stimulation. Electrical neuralstimulation can be delivered using any of a nerve cuff,intravascularly-fed lead, or transcutaneous electrodes.

A therapy embodiment involves preventing and/or treating ventricularremodeling. Activity of the autonomic nervous system is at least partlyresponsible for the ventricular remodeling which occurs as a consequenceof an MI or due to heart failure. It has been demonstrated thatremodeling can be affected by pharmacological intervention with the useof, for example, ACE inhibitors and beta-blockers. Pharmacologicaltreatment carries with it the risk of side effects, however, and it isalso difficult to modulate the effects of drugs in a precise manner.Embodiments of the present subject matter employ electrostimulatorymeans to modulate autonomic activity, referred to as anti-remodelingtherapy (ART). When delivered in conjunction with ventricularresynchronization pacing, also referred to as remodeling control therapy(RCT), such modulation of autonomic activity may act synergistically toreverse or prevent cardiac remodeling.

One neural stimulation therapy embodiment involves treating hypertensionby stimulating the baroreflex for sustained periods of time sufficientto reduce hypertension. The baroreflex is a reflex that can be triggeredby stimulation of a baroreceptor or an afferent nerve trunk. Baroreflexneural targets include any sensor of pressure changes (e.g. sensorynerve endings that function as a baroreceptor) that is sensitive tostretching of the wall resulting from increased pressure from within,and that functions as the receptor of the central reflex mechanism thattends to reduce that pressure. Baroreflex neural targets also includeneural pathways extending from the baroreceptors. Examples of nervetrunks that can serve as baroreflex neural targets include the vagus,aortic and carotid nerves.

Myocardial Stimulation Therapies

Various neural stimulation therapies can be integrated with variousmyocardial stimulation therapies. The integration of therapies may havea synergistic effect. Therapies can be synchronized with each other, andsensed data can be shared between the therapies. A myocardialstimulation therapy provides a cardiac therapy using electricalstimulation of the myocardium. Some examples of myocardial stimulationtherapies are provided below.

A pacemaker is a device which paces the heart with timed pacing pulses,most commonly for the treatment of bradycardia where the ventricularrate is too slow. If functioning properly, the pacemaker makes up forthe heart's inability to pace itself at an appropriate rhythm in orderto meet metabolic demand by enforcing a minimum heart rate. Implantabledevices have also been developed that affect the manner and degree towhich the heart chambers contract during a cardiac cycle in order topromote the efficient pumping of blood. The heart pumps more effectivelywhen the chambers contract in a coordinated manner, a result normallyprovided by the specialized conduction pathways in both the atria andthe ventricles that enable the rapid conduction of excitation (i.e.,depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the sino-atrial node to the atrial myocardium,to the atrio-ventricular node, and thence to the ventricular myocardiumto result in a coordinated contraction of both atria and bothventricles. This both synchronizes the contractions of the muscle fibersof each chamber and synchronizes the contraction of each atrium orventricle with the contralateral atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Pathology of these conduction pathways and otherinter-ventricular or intra-ventricular conduction deficits can be acausative factor in heart failure, which refers to a clinical syndromein which an abnormality of cardiac function causes cardiac output tofall below a level adequate to meet the metabolic demand of peripheraltissues. In order to treat these problems, implantable cardiac deviceshave been developed that provide appropriately timed electricalstimulation to one or more heart chambers in an attempt to improve thecoordination of atrial and/or ventricular contractions, termed cardiacresynchronization therapy (CRT). Ventricular resynchronization is usefulin treating heart failure because, although not directly inotropic,resynchronization can result in a more coordinated contraction of theventricles with improved pumping efficiency and increased cardiacoutput. A CRT example applies stimulation pulses to both ventricles,either simultaneously or separated by a specified biventricular offsetinterval, and after a specified atrio-ventricular delay interval withrespect to the detection of an intrinsic atrial contraction or deliveryof an atrial pace.

CRT can be beneficial in reducing the deleterious ventricular remodelingwhich can occur in post-MI and heart failure patients. Presumably, thisoccurs as a result of changes in the distribution of wall stressexperienced by the ventricles during the cardiac pumping cycle when CRTis applied. The degree to which a heart muscle fiber is stretched beforeit contracts is termed the preload, and the maximum tension and velocityof shortening of a muscle fiber increases with increasing preload. Whena myocardial region contracts late relative to other regions, thecontraction of those opposing regions stretches the later contractingregion and increases the preload. The degree of tension or stress on aheart muscle fiber as it contracts is termed the afterload. Becausepressure within the ventricles rises rapidly from a diastolic to asystolic value as blood is pumped out into the aorta and pulmonaryarteries, the part of the ventricle that first contracts due to anexcitatory stimulation pulse does so against a lower afterload than doesa part of the ventricle contracting later. Thus a myocardial regionwhich contracts later than other regions is subjected to both anincreased preload and afterload. This situation is created frequently bythe ventricular conduction delays associated with heart failure andventricular dysfunction due to an MI. The increased wall stress to thelate-activating myocardial regions is most probably the trigger forventricular remodeling. By pacing one or more sites in a ventricle nearthe infarcted region in a manner which may cause a more coordinatedcontraction, CRT provides pre-excitation of myocardial regions whichwould otherwise be activated later during systole and experienceincreased wall stress. The pre-excitation of the remodeled regionrelative to other regions unloads the region from mechanical stress andallows reversal or prevention of remodeling to occur. Cardioversion, anelectrical shock delivered to the heart synchronously with the QRScomplex, and defibrillation, an electrical shock delivered withoutsynchronization to the QRS complex, can be used to terminate mosttachyarrhythmias. The electric shock terminates the tachyarrhythmia bysimultaneously depolarizing the myocardium and rendering it refractory.A class of CRM devices known as an implantable cardioverterdefibrillator (ICD) provides this kind of therapy by delivering a shockpulse to the heart when the device detects tachyarrhythmias. Anothertype of electrical therapy for tachycardia is anti-tachycardia pacing(ATP). In ventricular ATP, the ventricles are competitively paced withone or more pacing pulses in an effort to interrupt the reentrantcircuit causing the tachycardia. Modern ICDs typically have ATPcapability, and deliver ATP therapy or a shock pulse when atachyarrhythmia is detected. ATP may be referred to as overdrive pacing.Other overdrive pacing therapies exist, such as intermittent pacingtherapy (IPT), which may also be referred to as a conditioning therapy.

Remote Physiological Sensing

Various embodiments of implanted neuromodulation devices usephysiological sensing to enhance therapies or diagnostics. For example,various embodiments provide a therapy based on rate, a therapy tied to acardiac cycle, a therapy tied to antitachycardia pacing (ATP) detection,a therapy tied to an average heart rate, a therapy tied to heart ratevariability (HRV), or a therapy tied to other cardiac diagnostics.Various embodiments provide input such as these to an implantedneuromodulation device without implanted cardiac leads.

Remote sensing of cardiac activity, cardiac pacing, laryngeal vibration,cough and/or other electromechanical physiological activity can provideinput into neuromodulation titration algorithms, neuromodulation therapydriver algorithms, neuromodulation heart failure diagnostics and otherdiagnostics and features. FIG. 1 illustrates various technologies forsensing physiologic signals used in various embodiments of the presentsubject matter. For example, remote physiological sensing 100, such asmay be used to provide a closed loop therapy or provide diagnostics, maybe performed using an electrode or may be performed using anaccelerometer (XL) 102. An electrode used to remotely sense cardiacactivity can be used to detect heart rate 103, to detect an AV interval104, to detect paces provided by a cardiac rhythm management (CRM)device 105, to detect antitachycardia pacing (ATP) 106, or to measureheart rate variability (HRV) 107. These examples are not intended to bean exclusive listing, as remotely sensed cardiac activity can be used ina variety of algorithms. An accelerometer may be used to remotely sensecardiac activity, and thus may be used to detect heart rate 108 or todetect an AV interval 109. An accelerometer may also be used to detectlaryngeal vibrations 110, cough 111 or respiratory activity 112, whichcan serve as feedback or other input for a neural stimulation therapysuch as a vagus nerve stimulation therapy.

FIG. 2 illustrates an implantable neural stimulator 213 and animplantable CRM device 214, according to various embodiments. Forexample, the neural stimulator 213 may be configured to stimulate avagus nerve in the cervical region, as illustrated in the figure.Examples of CRM devices include pacemakers, anti-arrhythmia devices suchas defibrillators and anti-tachycardia devices, and devices to delivercardiac resynchronization therapy (CRT). The illustrated neuralstimulator 213 has a neural stimulation lead 215 for use to deliverneural stimulation. The illustrated lead embodiment has a nerve cuffelectrode 216. Other lead embodiments provide transvascular stimulationof the nerve (e.g. stimulation of the vagus nerve from the internaljugular vein). In some embodiments, the neural stimulation lead 215 hasneural sensing capabilities, and/or remote sensing capabilities (e.g.accelerometer and/or electrode sensing). Some embodiments of a neuralstimulator 213 have a stub lead 217 to provide remote sensingcapabilities. The illustrated CRM device 214 includes a right atriallead 218 and a right ventricle lead 219. Other leads, additional leads,or fewer leads may be used for various device embodiments. In someembodiments, the neural stimulator 213 is a vagal nerve stimulator, suchas generally illustrated in FIG. 2. In some embodiments, the neuralstimulator is a spinal cord stimulator.

According to some embodiments, the neural stimulator device is the onlyimplanted medical device in the patient. In some embodiments, thepatient is implanted with both the neural stimulator device and the CRMdevice. Some embodiments provide communication between the neuralstimulator and the CRM device. The communication may be wireless or maybe through a wired connection such as a tether between the two devices.In some embodiment the neural stimulator operates without communicatingwith the CRM device, and thus independently senses paces, heart rate,and the like.

Various embodiments of the present subject matter use an accelerometerto remotely sense Heart Rate Variability (HRV) and perform Heart Failure(HF) diagnostics. HRV and other HF diagnostics may be based on thetiming between R-waves. Some embodiments store the S1 interval dataobtained from heart sounds and use this data for HRV diagnostics in lieuof R-wave intervals.

An accelerometer in an implanted medical device can be used to ascertainheart sounds. Known type heart sounds include the “first heart sound” orS1, the “second heart sound” or S2, the “third heart sound” or S3, the“fourth heart sound” or S4, and their various sub-components. Heartsounds can be used in determining a heart failure status. The firstheart sound (S₁), is initiated at the onset of ventricular systole andconsists of a series of vibrations of mixed, unrelated, low frequencies.S₁ is chiefly caused by oscillation of blood in the ventricular chambersand vibration of the chamber walls. The intensity of S₁ is primarily afunction of the force of the ventricular contraction, but also of theinterval between atrial and ventricular systoles. The second heart sound(S₂), which occurs on closure of the semi-lunar valves, is composed ofhigher frequency vibrations, is of shorter duration and lower intensity,and has a more “snapping” quality than the first heart sound. The secondsound is caused by abrupt closure of the semi-lunar valves, whichinitiates oscillations of the columns of blood and the tensed vesselwalls by the stretch and recoil of the closed valve. The third heartsound (S₃), which is more frequently heard in children with thin chestwalls or in patients with rapid filling wave due to left ventricularfailure, consists of a few low intensity, low-frequency vibrations. Itoccurs in early diastole and is believed to be due to vibrations of theventricular walls caused by abrupt acceleration and deceleration ofblood entering the ventricles on opening of the atrial ventricularvalves. A fourth or atrial sound (S₄), consisting of a few low-frequencyoscillations, is occasionally heard in normal individuals. It is causedby oscillation of blood and cardiac chambers created by atrialcontraction. Accentuated S₃ and S₄ sounds may be indicative of certainabnormal conditions and are of diagnostic significance. For example, amore severe HF status tends to be reflected in a larger S₃ amplitude.The term “heart sound” hereinafter refers to any heart sound (e.g., S1)and any components thereof (e.g., M1 component of S1, indicative ofMitral valve closure). S1, S2 and maybe S3 sounds may be distinguishedfrom the accelerometer signal. “Heart sounds” include audible mechanicalvibrations caused by cardiac activity that can be sensed with amicrophone and audible and inaudible mechanical vibrations caused bycardiac activity that can be sensed with an accelerometer.

Patangay et al. (US 20080177191), which is incorporated herein byreference in its entirety, discuss heart sounds and a relationshipbetween heart sounds and both QRS wave and left ventricular pressure.FIG. 3 illustrates heart sounds S1 and S2 such as may be detected usingan accelerometer; and FIG. 4 illustrates a relationship between heartsounds and both the QRS wave and left ventricular pressure.

A rate determination can be made by calculating the interval between S1sounds or other heart sounds (e.g. S2 to S2, or S3 to S3 or S4 to S4. S1is used as an example. FIG. 5 illustrates an embodiment of a method forcalculating an interval between heart sounds, used to determine heartrate. A timer is initialized, and the method waits for a detected S1sound. An interval is calculated between successive S1 sounds.

Average heart rate over a period of time can be determined once the S1intervals are calculated. Various embodiments provide cardiac rateaverages over discreet periods of time based on the S1 sound or the S2heart sound. FIG. 6 illustrates an embodiment of a method for usingheart sounds to calculate an average rate or to calculate HRV.Calculated intervals between heart sounds (e.g. S1 sounds) are stored. Aplurality of sample intervals are stored, and are used to calculate anaverage heart rate over a number of samples. The plurality of sampleintervals may be used to calculate a measure of heart rate variability.

A neural stimulation therapy may intermittently apply neuralstimulation. Various embodiments trend the average heart rate for whenthe neural stimulation is ON and when the neural stimulation is OFF.FIG. 7 illustrates an embodiment of a method for using heart sounds todetermine heart rate during time periods with neural stimulation andtime periods without neural stimulation. For example, some embodimentsapply neural stimulation with a duty cycle with an ON portion (e.g. atrain of pulses for approximately 10 seconds for each minute) and an OFFportion (e.g. approximately 50 seconds). The present subject matter isnot limited to embodiments with a 10 second ON portion and a 50 secondOFF portion, as other timing for the ON portion and/or the OFF portionmay be used. Thus, in the illustrated embodiment, neural stimulation isapplied for about 10 seconds at 720. As represented at 721, the numberof detected S1 sounds is identified during these ten seconds of appliedneural stimulation. At 722, after the 10 seconds of neural stimulation,the neural stimulation is disabled for the OFF portion of the duty cycle(e.g. about 50 seconds). As represented at 723, the number of detectedS1 sounds is identified during the period of disabled neuralstimulation, before neural stimulation is again applied at 720. Theoverall heart rate (HR) can be calculated, as well as the heart rateduring periods of applied neural stimulation (HR₁₀) and periods withoutneural stimulation (HR₅₀). Each of these heart rates can be averagedover various predetermined periods of time. For example, the overallheart rate (HR) may be averaged over each minute, over a fraction of theminute, or over multiple minutes. The heart rate during periods ofapplied neural stimulation (HR₁₀) may be averaged over the entireduration of a neural stimulation episode (e.g. 10 seconds), over afraction of each neural stimulation episode, or over multiple neuralstimulation episodes. The heart rate periods without neural stimulation(HR₅₀) may be averaged over the entire duration of an episode ofdisabled neural stimulation (e.g. 50 seconds), over a fraction of eachepisode of disabled neural stimulation, or over multiple episodes ofdisabled neural stimulation. Additionally, HRV may be determined over aperiod that includes both times with and without neural stimulation(HRV), over a period of time only when neural stimulation is applied(HRV₁₀), or over a period of time only when neural stimulation is notapplied (HRV₅₀). The trending of heart rate, HRV, left ventricularejection time (LVET) (S1 to S2), AV Delay, and the like can be performedusing heart sounds or remote ECG analysis.

According to various embodiments, a neural stimulation therapy isaltered or suspended upon detection of an arrhythmia. Heart soundintervals (e.g. S1 intervals) can be used to remotely detect aventricular arrhythmia. FIG. 8 illustrates an embodiment of a method forusing heart sounds to detect arrhythmia. At 824, neural stimulation isapplied for a period of time. During the period of time with neuralstimulation, S1 sounds are monitored to detect for an arrhythmia, asrepresented at 825. An arrhythmia may be detected by fast beats or by aloss of signal caused by the amplitudes of the sound signal droppingbelow the S1 threshold during fibrillation. If no arrhythmia isdetected, the illustrated method loops back to 824 to continue to applyneural stimulation. At 826, in response to a detected arrhythmia, theneural stimulation is modified or disabled. After modifying or disablingthe neural stimulation, S1 sounds are monitored to determine if thearrhythmia breaks. If the arrhythmia continues, the illustrated methodreturns back to 824. An arrhythmia break may be detected by slow beats,or by reacquiring a signal caused by the sound signal amplitude risingabove the S1 threshold after the arrhythmia breaks.

FIG. 9 illustrates an embodiment of a method for modulating neuralstimulation based on heart rate determined using heart sounds. Forexample, some embodiments apply neural stimulation for approximately 10seconds for each minute. Thus, in the illustrated method, neuralstimulation is applied for about 10 seconds at 928. As represented at929, the number of detected S1 sounds is identified during these tenseconds of applied neural stimulation. At 930, after the 10 seconds ofneural stimulation, the neural stimulation is disabled for about 50seconds. As represented at 931, the number of detected S1 sounds isidentified during the period of disabled neural stimulation, beforeneural stimulation is again applied at 928. At 932, a heart rate changeis determined using the S1 sounds detected during the neuralstimulation; and at 933, a heart rate change is determined using the S1sounds detected during times without neural stimulation. These heartrate changes are used to modify the neural stimulation, as generallyillustrated at 934. The modification to the neural stimulation may bebased on short term heart rate changes, long term heart rate changes, ora combination of both short and long term heart rate changes. Themodification of the neural stimulation can be based on response tophysiological need (exercise, stress) or need to change dosing due tochange in health status (lower HR due to better HF). By way of example,and not limitation, some embodiments deliver neural stimulation thatdoes not significantly alter heart rate. The therapy intensity (e.g.amplitude of the stimulation signal) may be reduced if the neuralstimulation is consistently associated with an undesired heart ratechange; or if an acute change in heart rate occurred during the latterportion of the ON time, the duration of the ON time could be altered orthe intensity of the therapy (e.g. amplitude of the stimulation signal)may be reduced during the latter portion of the ON time. In someembodiments, a determination of a long term change in heart rate (e.g.lower heart rate due to improvement in heart failure) causes the deviceto change to a maintenance dose mode of therapy (e.g. delivering therapyfor only a couple of hours a day). Various embodiments monitor for adivergence between the chronic average heart rate during the ON periodand the chronic average heart rate during the OFF period, or otherunexpected things, that may require a different therapy response.

Various embodiments of the present subject matter use an electrode toremotely sense cardiac activity. FIG. 10 illustrates an embodiment of acombined neural lead 1035 with dedicated neural stimulation electrodesand cardiac electrogram sensing electrodes (unipolar to can or bipolar).The illustrated lead includes a strain relief cuff 1036, and a pluralityof electrodes 1037. The plurality of electrodes 1037 includes a neuralelectrode cuff 1038 that includes both neural therapy electrodes 1039used to deliver neural stimulation and neural sensing electrodes 1040used to detect action potentials in the nerve. The plurality ofelectrodes in the illustrated lead embodiment also includes cardiac ECGsensing electrodes 1041 (e.g. electrodes to remotely sense cardiacactivity). The cardiac ECG sensing electrodes may either be bipolarelectrodes or unipolar electrodes to can.

Some embodiments of the neural stimulator 213 in FIG. 2 have eightelectrical contacts. As illustrated in FIG. 10, four of the contacts areused for CRM sensing electrodes 1041, two of the contacts are used tosense action potentials in nerves 1040, and two of the contacts are usedto stimulate nerves 1039. Other embodiments may be used. For example,some nerves are stimulated using tripolar electrodes. Fewer CRM sensingelectrodes 1041 may be used to accommodate more neural stimulationelectrodes. Neural sense electrodes could be designed into the cuff asshown, or as separate cuffs. The electrodes for neural therapy couldalso be used for neural sensing or CRM sensing. CRM sensing could benarrow field vector sensing between pairs of electrodes on the lead orcould be wide field vector sensing between lead electrodes and can.Narrow field vectors may have advantages in rate determination, whereaswide field vector may provide a surrogate for surface ECG.

FIG. 11 illustrates an embodiment of an implantable neural stimulationdevice 1113 with a neural stimulation lead 1115 and a separate sensingstub lead 1117 used to remotely detect cardiac activity. The neuralstimulation lead 1115 may include the cuff design illustrated in FIG.10, for example.

Various embodiments incorporate the CRM sensing electrode into a portplug. FIGS. 12A-12B illustrate an embodiment of a device 1213 withnarrow field vector sensing capabilities using a port electrode and can.The device 1213 includes a header 1242 configured to receive a stub lead1243. The stub lead and header have an electrical contact 1244. Theillustrated stub lead includes a retention cuff 1245 and a sensingelectrode 1246.

Various embodiments place the CRM sensing electrode or electrodes on alonger lead body in order to allow for wider field sensing. FIG. 13illustrates an embodiment of a device 1313 with wide field vectorsensing capabilities using a distal lead electrode and can. Theillustrated device includes a header configured to receive the sensinglead 1347 with one or more sensing electrode(s) 1348. The sensing lead1347 may tunnel next to the neural therapy lead or elsewhere in thebody.

A common platform for both a stand-alone neural device and a combinationneural and CRM device can be designed if remote CRM sensing capabilitiesare available. For example, the A or LV port may be modified for use asthe neural output and the RV port may be maintained for sensing. The RVport could be connected to a small “stub” lead with a sensing electrodethat allows for a narrow field vector sensing. A longer lead with asensing electrode could also be placed in the RV port for a wider fieldvector sensing. The lead could be tunneled to any place under the skinand is not placed inside the cardiac tissue.

A sensing electrode could be incorporated into a stub lead or into theport itself in order to facilitate remote ECG sensing. Depending on thegain and signal to noise ratio, the remote ECG sensing could be used bya remote cardiac rate determiner, a remote R-wave detector or more.

Remotely determining rate may allow rate feedback to be part of aclosed-loop neural stimulation therapy. By way of example and notlimitation, neural stimulation could be applied only when the averagerate has been above a threshold for a period of time. As R-waves havethe highest amplitude in the ECG signal, the R-waves can be remotelysensed to determine rate. The present subject matter is not limited tousing R-waves, as other waves (e.g. T-waves) may be detected and used todetermine rate.

FIG. 14 illustrates remote cardiac R-wave detection for remote cardiacrate determination, according to various embodiments. A thresholdcrossing method can be applied to identify R-waves, which enables thedetermination of heart rate, average heart rate, HRV, and the like. Morecomplex algorithms can be used to identify QRS components and AV delaysand other diagnostics (see, for example, Yun-Chi Yeh and Wen-June Wang,“QRS Complexes Detection for ECG Signal: The difference operationmethod.” Computer Methods and Programs in Biomedicine, Volume 91, Issue3 (September 2008), Pages 245-254.)

FIG. 15 illustrates an embodiment of a method for monitoring heart ratefor feedback to a neural stimulation therapy. The illustrated embodimentdetermines heart rate during time periods with neural stimulation andtime periods without neural stimulation. For example, some embodimentsapply neural stimulation with a duty cycle (e.g. an ON portion ofapproximately 10 seconds for each minute and an OFF portion ofapproximately 50 seconds). Thus, in the illustrated embodiment, neuralstimulation is applied for about 10 seconds at 1549. As represented at1550, the number of R-waves or PQRS waves are identified during theseten seconds of applied neural stimulation. At 1551, after the 10 secondsof neural stimulation, the neural stimulation is disabled for about 50seconds. As represented at 1552, the number of R-waves or PQRS waves areidentified during the period of disabled neural stimulation, beforeneural stimulation is again applied at 1549. The remote sensing ofcardiac activity using electrodes provides an approximation of a surfaceECG. The overall heart rate (HR) can be calculated, as well as the heartrate during periods of applied neural stimulation (HR₁₀) and periodswithout neural stimulation (HR₅₀). Each of these heart rates can beaveraged over various predetermined periods of time. For example, theoverall heart rate (HR) may be averaged over each minute, over afraction of the minute, or over multiple minutes. The heart rate duringperiods of applied neural stimulation (HR₁₀) may be averaged over theentire duration of a neural stimulation episode (e.g. 10 seconds), overa fraction of each neural stimulation episode, or over multiple neuralstimulation episodes. The heart rate periods without neural stimulation(HR₅₀) may be averaged over the entire duration of an episode ofdisabled neural stimulation (e.g. 50 seconds), over a fraction of eachepisode of disabled neural stimulation, or over multiple episodes ofdisabled neural stimulation. Additionally, HRV may be determined over aperiod that includes both times with and without neural stimulation(illustrated in the figure as HRV), over a period of time only whenneural stimulation is applied (illustrated in the figure as HRV₁₀), orover a period of time only when neural stimulation is not applied(illustrated in the figure as HRV₅₀). The trending of heart rate, HRV,AV Delay, and the like can be performed using heart sounds or remote ECGanalysis.

FIG. 16 illustrates an embodiment of a method for trending heart rateinformation for a neural stimulation therapy. In the illustratedembodiment, neural stimulation is applied for about 10 seconds at 1653.As represented at 1654, the ECG is monitored to identify the number ofR-waves or PQRS waves during these ten seconds of applied neuralstimulation. At 1655, after the 10 seconds of neural stimulation, theneural stimulation is disabled for about 50 seconds. As represented at1656, the ECG is monitored to identify the number of R-waves or PQRSwaves during the period of disabled neural stimulation, before neuralstimulation is again applied at 1653.

The overall heart rate (HR) can be calculated, as well as the heart rateduring periods of applied neural stimulation (HR₁₀) and periods withoutneural stimulation (HR₅₀). Each of these heart rates can be averagedover various predetermined periods of time. For example, the overallheart rate (HR) may be averaged over each minute, over a fraction of theminute, or over multiple minutes. The heart rate during periods ofapplied neural stimulation (HR₁₀) may be averaged over the entireduration of a neural stimulation episode (e.g. 10 seconds), over afraction of each neural stimulation episode, or over multiple neuralstimulation episodes. The heart rate periods without neural stimulation(HR₅₀) may be averaged over the entire duration of an episode ofdisabled neural stimulation (e.g. 50 seconds), over a fraction of eachepisode of disabled neural stimulation, or over multiple episodes ofdisabled neural stimulation. Additionally, HRV may be determined over aperiod that includes both times with and without neural stimulation(HRV), over a period of time only when neural stimulation is applied(HRV₁₀), or over a period of time only when neural stimulation is notapplied (HRV₅₀). The trending of heart rate, HRV, AV Delay, and the likecan be performed using heart sounds or remote ECG analysis.

According to various embodiments, a neural stimulation therapy isaltered or suspended upon detection of an arrhythmia. FIG. 17illustrates an embodiment of a method for detecting arrhythmia. At 1757,neural stimulation is applied for a period of time. During the period oftime with neural stimulation, the electrical cardiac activity of theheart (e.g. ECG) is remotely monitored to detect for an arrhythmia, asrepresented at 1758. An arrhythmia may be detected by fast beats or by aloss of signal caused by the amplitudes of the sound signal droppingbelow the R-wave threshold during fibrillation. If no arrhythmia isdetected, the illustrated method returns back to 1757 to continue theneural stimulation. At 1759, in response to a detected arrhythmia, theneural stimulation is modified or disabled. After modifying or disablingthe neural stimulation, the electrical cardiac activity of the heart(e.g. ECG) is remotely monitored to determine if the arrhythmia breaks.If the arrhythmia continues, the illustrated method returns back to1757. An arrhythmia break may be detected by slow beats, or byreacquiring a signal caused by the sound signal amplitude rising abovethe R-wave threshold after the arrhythmia breaks.

FIG. 18 illustrates an embodiment of a method for modulating a neuralstimulation therapy. For example, some embodiments apply neuralstimulation for approximately 10 seconds for each minute. Thus, in theillustrated method, neural stimulation is applied for about 10 secondsat 1881. As represented at 1882, the number of detected R-waves isidentified during these ten seconds of applied neural stimulation. At1883, after the 10 seconds of neural stimulation, the neural stimulationis disabled for about 50 seconds. As represented at 1884, the number ofdetected R-waves is identified during the period of disabled neuralstimulation, before neural stimulation is again applied at 1881. At1885, a heart range change or an AV interval change is determined usingthe R-waves detected during the neural stimulation; and at 1886, a heartrate change or AV interval change is determined using the R-wavesdetected during times without neural stimulation. These changes are usedto modify the neural stimulation, as generally illustrated at 1887. Themodification to the neural stimulation may be based on short termchanges, long term changes, or a combination of both short and long termchanges. The modification of the neural stimulation can be based onresponse to physiological need (exercise, stress) or need to changedosing due to change in health status (lower heart rate due to betterheart failure status). By way of example, and not limitation, someembodiments deliver neural stimulation that does not significantly alterheart rate. The therapy intensity (e.g. amplitude of the stimulationsignal) may be reduced if the neural stimulation is consistentlyassociated with an undesired heart rate change; or if an acute change inheart rate occurred during the latter portion of the ON time, theduration of the ON time could be altered or the intensity of the therapy(e.g. amplitude of the stimulation signal) may be reduced during thelatter portion of the ON time. In some embodiments, a determination of along term change in heart rate (e.g. lower heart rate due to improvementin heart failure) causes the device to change to a maintenance dose modeof therapy (e.g. delivering therapy for only a couple of hours a day).Various embodiments monitor for a divergence between the chronic averageheart rate during the ON period and the chronic average heart rateduring the OFF period, or other unexpected things, that may require adifferent therapy response. More complex algorithms can be used toidentify QRS components, P-wave, T-wave and AV Delays. HRV diagnosticinformation can be obtained by, monitoring, storing and analyzing theintervals between R-wave detections. Some CRM devices use timing betweenR-waves to provide HRV and other HF diagnostics. R-waves can bedetermined from remotely-sensed ECG.

Some neural stimulation devices alter the neural stimulation therapy forcardiac pacing. Thus, if a neural stimulator and a CRM device are notdesigned to communicate with each other, then the neural stimulatorincludes a remote cardiac pace detector. Pace detection may be useful inan independent neural stimulation system implanted in an individual whoalso has a CRM device implant.

FIG. 19 illustrates an embodiment of remote cardiac pace detectioncircuitry. The input signal 1988 comes from sense electrodes, and passesthrough a bandpass filter 1989 illustrated with a center frequency ofapproximately 30 KHz. The pace detection circuitry creates two detectionsignals. A first detection signal 1990 is generated when the rising edgeof a pace pulse passes through the bandpass filter at a level greaterthan the positive threshold 1991. A second detection signal 1992 isgenerated when the falling edge of a pace pulse passes through thebandpass filter at a level more negative than the negative threshold1993. The combination of the two detection signals, as received by thedigital state machine or microcontroller 1994, results in a pacedetection. For each of the illustrated detection signals, theillustrated circuit includes a cascaded amplifier 1995A and 1995B thatfunctions as a comparator, and a sample and hold circuit 1996A and 1996Bclocked by a 1 MHz system clock.

FIG. 20 illustrates a flow diagram of an embodiment for detecting pulsesusing the pace detection circuitry illustrated in FIG. 19. State 1,represented at 2001, is a state in which the circuit waits for the firstpulse. If the first pulse is positive, three timers are started and thecircuit enters State 2P, represented at 2002. These timers include afirst timer identified as a really short timer (RST), a second timeridentified as a short timer (ST), and a third timer identified as a longtimer (LT). The names given to these timers represent a manner ofdegree, and are not intended to be limiting. State 2P is a state inwhich the circuit waits for the first timer (RST) to expire. The end ofthe time represented by RST represents a beginning of a time frame foran expected negative pulse to occur after the positive pulse sensed at2001. Once the first timer expires, the circuit enters State 3P,represented at 2003, which is a state in which the circuit waits for theexpected negative pulse. If the second timer (ST) expires without anegative pulse, the circuit returns to State 1 at 2001. If a negativepulse occurs, the circuit enters State 4, represented at 2004, which isa state in which the circuit waits for the expiration of the third timer(LT). When the third timer (LT) expires, the circuit returns to State 1.If the first pulse is negative, three timers are started and the circuitenters State 2N, represented at 2005. These timers include a first timeridentified as a really short timer (RST), a second timer identified as ashort timer (ST), and a third timer identified as a long timer (LT). Thenames given to these timers represent a manner of degree, and are notintended to be limiting. Also, the timers associated with the negativepulse may or may not be the same as the timers associated with thepositive pulse. State 2N is a state in which the circuit waits for thefirst timer (RST) to expire. The end of the time represented by RSTrepresents a beginning of a time frame for an expected positive pulse tooccur after the negative pulse sensed at 2001. Once the first timerexpires, the circuit enters State 3N, represented at 2006, which is astate in which the circuit waits for the expected positive pulse. If thesecond timer (ST) expires without a positive pulse, the circuit returnsto State 1 at 2001. If a positive pulse occurs, the circuit enters State4, represented at 2004, which is a state in which the circuit waits forthe expiration of the third timer (LT). When the third timer (LT)expires, the circuit returns to State 1. This algorithm is looking forpulses of opposite polarity that occur between RST and ST apart, whereRST and ST are the respectively the minimum and maximum expected pacingpulse widths. Once a pace is detected, the algorithm waits a timecorresponding to the third timer (LT) from the beginning of the pacebefore looking for another pace, where the time corresponding to thethird timer (LT) is the expected minimum pacing interval.

Various embodiments remotely detect which heart chamber is being paced.In some embodiments, the pacemaker is programmed with different pacingpulse widths for each chamber (e.g. 0.40 ms for an atrial pace, 0.50 msfor a right ventricular pace and 0.45 for a left ventricular pace). Inthis embodiment, for example, multiple short timers (ST in the abovealgorithm) may be implemented to identify each specific programmed pulsewidth. In some embodiments, input from a remote ECG sensor is used todetermine whether the detected pace pulse is associated in time with aP-wave or an R-wave on the ECG.

To account for dual-chamber pacing and CRT pacing as well asrate-responsive pacing or loss of capture, more complex algorithms canbe used to identify QRS components, P-wave, T-wave and AV Delays viaremote ECG analysis. A wide vector between the neural lead and the canof the implanted neural stimulator or a small vector from a stub lead tothe can of the implanted neural stimulator can be used to show the QRScomponents under the proper gain. HRV diagnostic information can beobtained by monitoring, storing and analyzing the intervals betweenR-wave detections.

According to various embodiments, the neural stimulator is programmed toknow that the pacemaker is a single chamber device and therefore declareany detected pace as an RV-pace. Some embodiments declare any detectedpace followed by an R-wave sense as a captured RV-pace. FIG. 21illustrates an embodiment of a method for correlating a detected pace toa right ventricle pace. A pace is detected at 2107. The pace may bedetected using the system illustrated in FIGS. 19-20. ECG circuitry 2108remotely senses cardiac electrical activity, and the remotely sensed ECGmay be used to determine an R-wave. As illustrated at 2109, if the paceoccurs close in time to the sensed R-wave, then the RV-pace is declared.All other detected paces would be declared as a non-captured RV-pace.The neural stimulation therapy may be altered based on capture ornon-capture. In embodiments that remotely sense an ECG and discriminateP-wave or determine cardiac cycle timing based on heart sounds, adetected pace may be assigned as a captured A-pace, non-captured A-pace,captured RV-pace or non-captured RV-pace.

FIG. 22 illustrates an embodiment of a method for detectingantitachycardia pacing (ATP). Some embodiments assume that no cardiacpacing will occur for at least 5 seconds prior to an ATP burst since thepatient would be in an arrhythmia. As illustrated, the embodiment waitsfor a detected pace at 2210. When the pace is detected, anantitachycardia pacing (ATP) count is incremented. At 2211, it isdetermined if there has been at least 5 seconds (or other predeterminedperiod) since the last pace. If there has not been at least 5 secondssince the last pace, then it is assumed that the patient is not in anarrhythmia, the ATP count is cleared and the process returns to 2210. Ifthere has been at least 5 seconds since the last pace, then the processwaits for the next pace detect at 2212. When the next pace is detected,the ATP count is incremented. At 2213, it is determined if there hasbeen at least 330 ms since the last pace. If there has been at least 330ms (or other predetermined period) since the last pace, then it isdetermined that ATP is not present, the ATP count is cleared, and theprocess returns to 2210. If there has not been at least 330 ms (or otherpredetermined period), it is determined at 2214 whether the ATP count isgreater than a threshold. If the ATP count is greater than thethreshold, an ATP is declared. If the ATP count is not greater than thethreshold, then the process returns to 2212 to wait for anothersubsequent pace that may be part of antitachycardia pacing. ATP may bereferred to as overdrive pacing. Other overdrive pacing therapies exist,such as intermittent pacing therapy (IPT), which may also be referred toas a conditioning therapy. Various embodiments detect an overdrivepacing therapy and modify neural stimulation if overdrive pacing isdetected.

FIG. 23 illustrates an embodiment of a method that uses antitachycardiapacing as an input to a neural stimulation therapy. A neural stimulationtherapy is applied at 2315, and at 2316 the remotely sensed cardiacactivity (e.g. ECG) is monitored for antitachycardia pacing. Ifantitachycardia pacing is detected, the neural stimulation is disabledor modified as illustrated at 2317 until a predetermined trigger tobegin the normal neural stimulation again. The trigger may be an expiredtimer. Some embodiments monitor ECG 2318 while the neural stimulation isdisabled or modified, and begin the normal stimulation when anarrhythmia is no longer detected. Some embodiments monitor for a highvoltage shock and return to delivering neural stimulation after the highvoltage shock.

Other embodiments to incorporate information from a rate sensor ratherthan assuming that no cardiac pacing will occur for at least 5 secondsprior to an ATP burst. In some embodiments, the ATP detection algorithmis invoked after the detected rate from the remote rate sensor surpassesa remote tachy detection threshold, and the determination of whether ithas been 5 seconds since the last pace could be removed from the remoteATP detection algorithm. Additional information from an activity sensorsuch as an accelerometer could further be used to refine the algorithmto screen out rate responsive pacing.

The sensitivity and the specificity of remote CRM information can beincreased by using information obtained from multiple sources (e.g.blended remote CRM information). Various embodiments blend inputs fromremote cardiac R-wave sensors, remote cardiac rate determiners, activitysensors or other sensors. Various embodiments blend cardiac senseresponse and cardiac pace response as well as inputs from remote cardiacR-wave sensors, remote cardiac rate determiners, activity sensors orother sensors. The pace location identification approach is one example.Some embodiments combine inputs from the leads and the accelerometer toremotely detect rate. For example, the detected ECG cardiac activity maybe blended with the detected heart rate information using anaccelerometer (indicative of the mechanical function of the heart).Electrical-mechanical dyssynchrony is a signature of heart failure andprovides diagnostic information for a device designed to treat heartfailure. The detected cardiac activity may be used to ascertain heartsounds.

Some neural stimulation therapies alter the therapy based on cardiacsensing and pacing. For example, some embodiments synchronize withholdor alter a neural stimulation therapy on a remotely detected sense, aremotely detected RV-sense, or remotely detected other chamber sense.Some embodiments apply withhold or alter a neural stimulation therapywhen the sensed cardiac rate is above a lower rate level (LRL)(indicative of a physiological need such as stress, exercise, and thelike). Some neural stimulation or autonomic modulation therapies mayacutely decrease heart rate. An embodiment includes a LRL cutoff belowwhich those therapies would be suspended to avoid lowering an alreadylow heart rate. Some embodiments provide a maximum sensing rate cutofffor delivering these therapies to avoid interactions between highintrinsic rates and a therapy that can alter conduction. Someembodiments deliver a short term neural stimulation therapy immediatelyafter a detected premature ventricular contraction (PVC) to alterconduction. Some embodiments apply, withhold or alter a neuralstimulation therapy when the average resting heart rate has changed by acertain amount (due to remodeling, worsening heart failure, change indrug regimen, and the like). Some embodiments apply, withhold or alterneural stimulation therapy when average AV Delay (from remote ECGanalysis) or average left ventricular ejection time (LVET) (from heartsound analysis) changes over time. Some embodiments apply, withhold oralter neural stimulation therapy upon remote arrhythmia detection(sensing rate above an arrhythmia threshold).

By way of example, one embodiment provides rapid therapy titration for aneural stimulation therapy when the sensing rate is above a certainrate. Some implementations of vagus nerve stimulation affect cardiacrate. As such, cardiac rate may be used as an input for therapytitration and, if cardiac heart rate is available via remote sensing,then therapy could be automatically titrated. Various embodimentstitrate the therapy to find the highest tolerable therapy that increasesheart rate, lengthens AV delay and the like, or to find the highesttherapy that does not alter or significantly alter heart rate, AV delayand the like.

FIG. 24 illustrates various embodiments of closed loop neuralstimulation that use detected pacing as an input. Various neuralstimulation therapies involve intermittent neural stimulation (e.g. aprogrammed duty cycle with a programmed period of neural stimulationfollowed by a programmed period without neural stimulation). Someembodiments, by way of example and not limitation, provide about 10seconds of neural stimulation followed by about 50 seconds withoutneural stimulation. At 2419, neural stimulation is applied (e.g. about10 seconds of stimulation). At 2420, pacing is monitored for the periodof time when neural stimulation is applied. The neural stimulation isdisabled at 2421, and pacing is monitored during the period of timewithout neural stimulation (e.g. about 50 seconds without neuralstimulation). At 2423, the process determines the change in the detectedright ventricle pacing during the period when neural stimulation isapplied. At 2424, the process determines the change in the detectedright ventricle pacing during the period when neural stimulation is notapplied. Neural stimulation parameter(s) can be modified based onshort-term changes, long-term changes, or combinations of short-term andlong-term changes. By way of example and not limitation, neuralstimulation therapy can trigger off of a change in detected rightventricle paces during neural stimulation, a ratio change if rightatrium pacing to right ventricle pacing, or a change in right ventriclepacing corresponding to accelerometer activity.

Some embodiments synchronize, withhold or alter neural stimulationtherapy on a remotely detected pace, remotely detected RV-pace, orremotely detected other chamber pace. Some embodiments apply, withholdor alter neural stimulation therapy when a pacing rate is above a LRLfor a sensed cardiac rate (indicative of a physiological need such asstress, exercise, etc). Some neural stimulation or autonomic modulationtherapies may acutely decrease heart rate. An embodiment includes a LRLcutoff below which those therapies would be suspended to avoid loweringan already low heart rate. Some embodiments provide a maximum sensingrate cutoff for delivering these therapies to avoid interactions betweenhigh intrinsic rates and a therapy that can alter conduction. Someembodiments deliver a short term neural stimulation therapy immediatelyafter a detected premature ventricular contraction (PVC) to alterconduction. Some embodiment apply, withhold or alter a neuralstimulation therapy when x % of the cardiac cycles have been paced for ay period of time. For example, a change in AV Delay may cause more orless RV pacing. It may be appropriate to change neural stimulationtherapy if there is an extended period of pacing or an extended periodof not pacing. Some embodiments apply, withhold or alter neuralstimulation when always pacing at rest which may indicate remodeling,worsening heart failure, a change in a drug regimen, and the like. Someembodiments apply, withhold or alter neural stimulation upon a remoteATP detection. Some embodiments provide a first heart failure therapyinvolving cardiac resynchronization therapy (CRT) and a second heartfailure therapy involving neural stimulation. The system may beprogrammed so that CRT has priority over the neural stimulation. If theloss of left ventricular pacing or biventricular pacing is lost, thenthe neural stimulation is suspended, or an AV parameter may be changed.The dose of the neural stimulation may be altered if the systemdetermines that the loss of pacing occurs during the latter portion ofthe ON portion of the neural stimulation period. The neural stimulationamplitude may be adjusted (e.g. ramped up) during the initial portion ofthe ON portion if loss of CRT is detected. Rather than using x % toapply, withhold or alter the neural stimulation therapy, someembodiments use another metric, such as a programmed number of cycles(e.g. four cycles) without or without a pace.

Respiration creates sounds that may be picked up by an accelerometerplaced close to the trachea. The accelerometer can be either in the canor on the vagal nerve lead. The location of the neural stimulation canand lead may not be conducive to using the minute ventilation systemcurrently employed in CRM products.

Breathing, snoring and other breathing noises have frequency componentswith the highest frequency about 2 KHz. Sampling rates of twice that ormore are required. Bandpass filtering from 200 Hz to 1500 Hz will covermost of the spectrum of interest. Narrower bandpass filtering of 250 Hzto 600 Hz may provide a better signal to noise ratio in the intendedimplanted environment. Also, multiple narrower bandpass filtering mayprovide unique information about respiration such as depth of breath, ordistinguishing cough and voice. FIG. 25 illustrates an example ofband-pass filtered tracheal sound (75 Hz to 600 Hz), as was illustratedby A. Yadollahi and Z. M. K. Moussavi, “Acoustical Respiratory Flow”,IEEE Engineering in Medicine and Biology, January/February 2007, pages56-61. Various embodiments may use a bandpass filtered tracheal soundsimilar to that illustrated in FIG. 25.

FIG. 26 illustrates an embodiment of a method for filtering trachealsound. At 2626, an accelerometer is monitored to provide an acousticsignal, and this acoustic signal is passed through a bandpass filter topass the acoustic signal corresponding to respiratory frequencies. Insome embodiments, the bandpass filter passes frequencies fromapproximately 75 Hz to approximately 1500 Hz. In some embodiments, thebandpass filter passes frequencies from approximately 75 Hz to 600 Hz.

FIG. 27 illustrates an embodiment of a method for titrating neuralstimulation. A neural stimulation therapy is applied at 2728. At 2729, abandpass filtered accelerometer signal is monitored in a sensing window(a period of time) after the neural stimulation pulse. At 2730, thefiltered accelerometer signal is used to determine whether laryngealvibration is above a threshold. As illustrated at 2731, some embodimentstitrate the neural stimulation therapy if the laryngeal vibration occurs“x” times out of “y” pulses during one duty cycle. In an embodimentwhere neural stimulation is delivered with an ON/OFF cycle and at 20 Hzfor 10 seconds for every ON period, 200 pulses are delivered every 10second dosing cycle. Laryngeal vibration may be detected after onlyhalf, or other value, of the pulses in a dosing cycle, or a patient maytolerate therapy if laryngeal vibration occurs in response to only 10 or50 of those 200 pulses. The present subject matter can work if laryngealvibration occurs at all during the ON portion. Various embodimentsautomatically titrate neural stimulation down if the number of laryngealvibration goes above the threshold.

Some neural stimulation therapies may be modulated or otherwisecontrolled based on breathing rate. For example, higher averagedbreathing rate could indicate stress or exercise and the neuromodulationtherapies could be enabled, modified, or disabled in response to achange in average breathing rate.

Some neural stimulation therapies may be modulated or otherwisecontrolled based on apneic event detection. For example, a breathingpattern indicative of Stokes-Cheney could trigger enabling, modifying,or disabling a neural stimulation therapy.

A number of methods have been proposed to detect apnea, particularlydetecting apnea using tracheal sounds. One such approach is discussed in“Apnea Detection by Acoustical Means,” Yadollahi, A.; Moussavi, Z.;Engineering in Medicine and Biology Society, 2006, EMBS '06, 28th AnnualInternational Conference of the IEEE, Aug. 30, 2006-Sep. 3, 2006, Pages4623-4626.

Some neural stimulation therapies may be modulated or otherwisecontrolled based on estimates of respiratory flow. Estimates of flow canbe made using analysis of tracheal sounds. A number of methods have beenproposed to estimate respiratory flow using tracheal sounds. One suchapproach is discussed in “A robust method for estimating respiratoryflow using tracheal sounds entropy,” Yadollahi, A; Moussavi, Z; M. K.,Biomedical Engineering, IEEE Transactions, Volume 53, Issue 4, April2006 Pages 662-668.

Sounds from the heart may interfere with efforts to analyze respiratorysounds. Respiratory sounds are almost free of the heart sounds effect ata frequency range over 300 Hz. However, there is overlap in thefrequency ranges for where most of the heart sound energy occurs (20 Hzto 200 Hz) and for where most of the respiratory sound energy occurs (75Hz to 600 Hz). Information about expiratory respiration can be lost ifthe respiratory sounds are analyzed at a frequency range over 300 Hz,whereas information about inspiratory respiration can be analyzed athigher frequencies (see Gavriely, N., Nissan, M., Rubin A. H. andCugall, D. W. “Spectral characteristics of chest wall breath sounds innormal subject,” Thorax, 11995, 50:1292-1300). Respiratory rate may bedetermined using the inspiratory sounds above 300 Hz since therespiratory sounds are mostly free of heart sounds at those rates,making analysis presumably easier. However, other respiratoryinformation would not be available if using chest wall breath sounds.There may be some shift in the spectral pattern using sounds from thetrachea and the paper. There may be some shift in the spectral patternusing sounds from the trachea and the may be enough information in the300 Hz to 600 Hz frequency range to determine both respiratory rate andflow.

Implanted devices have means to detect cardiac activity. Electricalactivity as determined from an ECG or sensing from intracardiac leadscan be used to identify the QRS complex. The S1 heart sounds arecorrelated with the end of the QRS. Analysis of the respiratory soundcould then blank or ignore the signal around the identified area forheart sound, or subtraction or other signal processing could beperformed for that segment of the signal to account for the heart sound.Mechanical activity of the heart can be determined and similar, orcomplementary, signal processing of the respiratory signal can beperformed.

Respiratory sensors may have a need to be calibrated for accuracy andcan be calibrated with the use of one or more breaths under definedconditions. A “learning” mode for calibration may be incorporated withinthe implanted device to individualize the analysis of the respiratorysound to the patient. This learning mode can be physician-initiated orperformed automatically by the device when certain criteria (e.g.meeting minimal activity).

Vagus nerve stimulation can elicit laryngeal vibration above astimulation threshold. Laryngeal vibration may be a tolerable sideeffect whose presence indicates therapy is being delivered. Laryngealvibration may be remotely detected using an accelerometer. An embodimentof a remote laryngeal vibration detector monitors the output of theaccelerometer after each neural stimulation pulse. If there is a signalon the accelerometer, then the detector can declare laryngeal vibration.

FIG. 28 illustrates an embodiment of a method for detecting laryngealvibration by monitoring an accelerometer filtered to a neuralstimulation frequency. At 2832, the neural stimulation burst is applied.The neural stimulation has a pulse frequency. At 2833, accelerometerdata is filtered to the neural stimulation pulse frequency. If thelaryngeal vibration is above a threshold, as determined at 2834, thenthe intensity of the neural stimulation therapy is titrated up or downat 2835.

FIG. 29 illustrates an embodiment of a method for controlling neuralstimulation. A neural stimulation therapy is initiated at 2936.Accelerometer data is monitored at 2937 to determine AV delay, orlaryngeal vibration, or coughing, or LVET. At 2938, it is determined ifthe accelerometer data is satisfying the criteria for the neuralstimulation therapy. If it is, the neural stimulation is maintained. Ifit is not, then the neural stimulation therapy is adjusted in an effortto bring the monitored accelerometer data into compliance with thecriteria for the neural stimulation therapy. If neural stimulation isprovided to deliver a maximum tolerable amplitude, an example ofcriteria for neural therapy titration includes increasing amplitudeuntil laryngeal vibration detection, continuing to increase amplitudeuntil coughing is detected, reducing the amplitude a step, verifyinglaryngeal vibration is still detected, and ending titration. Assumingthat laryngeal vibration indicates all nerve fibers have been captured,if neural stimulation is provided to deliver a lowest amplitude doeswith confirmation that therapy is being delivered, an example increasesamplitude until laryngeal vibration is detected, and titration is ended.This may include detecting laryngeal vibration, decreasing amplitudeuntil laryngeal vibration no longer is detect, increasing amplitude onestep, and verifying laryngeal vibration to confirm therapy delivery. Insome embodiments, this includes detecting coughing, decreasing amplitudeuntil coughing is no longer detected, and verifying laryngeal vibrationto confirm therapy delivery. Some embodiments increase amplitude untillaryngeal vibration is detected, back down amplitude one step to providea maximum amplitude dose without side effects, assuming therapyeffective without need to laryngeal vibration to confirm therapydelivery. Some embodiments increase amplitude until laryngeal vibrationis detected, back down amplitude one step, and confirm therapyeffectiveness using a change in AV delay or a change in LVET. The neuralstimulation therapy may be discontinued after predetermined conditionsare met.

Some embodiments monitor the accelerometer and filter for signal with afrequency corresponding to neural stimulation (e.g. bandpass filter fora 20 Hz signal). If there is laryngeal vibration due to neuralstimulation with a plurality of pulses where the frequency of the pulsesis 20 Hz, then that vibration will be modulated at 20 Hz. The bandpassfiltered 20 Hz signal could also be monitored only when neuralstimulation is being delivered. Some embodiments compare the bandpassfiltered signal with neural stimulation to the bandpass filtered signalwithout neural stimulation. If there is a 20 Hz signal on theaccelerometer when neural stimulation is being delivered, then thedetector can declare laryngeal vibration. The 20 Hz pulse frequency isan example. The bandpass filtering is tuned to the frequency of thepulse delivery. The frequency may be a programmable value and thefiltering should automatically adjust to whatever the programmedfrequency.

FIG. 30 illustrates an embodiment of a method for controlling neuralstimulation using a filtered accelerometer signal monitored over aneural stimulation burst. Neural stimulation may be delivered with aduty cycle that includes an ON phase and an OFF phase. At 3039, a neuralstimulation is applied during an ON phase of the duty cycle, and afiltered accelerometer signal is monitored during the ON phase of theduty cycle, as illustrated in 3040. At 3041, the filtered accelerometersignal is used to determine if coughing above a threshold is occurring.Various embodiments titrate neural stimulation if coughing occurs duringthe ON phase of the duty cycle. For example, the neural stimulationintensity may be reduced to avoid the cough.

Laryngeal vibration may be used to rapidly titrate a neural stimulationtherapy. A laryngeal vibration detector may be used to automaticallytitrate therapy up or down based on whether there is vibration. Thistitration could be performed at the time of implant, at follow-up visitsto a clinical setting, or in an ambulatory patient.

FIG. 31 illustrates an embodiment of a method for rapidly titratingneural stimulation therapy using accelerometer data. As illustrated,different information can be obtained from one accelerometer based onhow the output of the accelerometer is filtered. An accelerometer datasignal is monitored at 3143. As illustrated at 3144, a bandpass filtercorresponding to a heart sound (e.g. S1) is applied to the accelerometerdata signal. This information can be used to determine heart rate andother information based on rate. As illustrated at 3145, a bandpassfilter corresponding to a neural stimulation frequency is applied to theaccelerometer data signal. This may be used to detect the laryngealvibration attributed to neural stimulation. As illustrated at 3146, abandpass filter corresponding respiratory frequencies is applied to theaccelerometer data. This information can be used to titrate, initiate,or terminate neural stimulation.

Vagus nerve stimulation can elicit coughs above a stimulation threshold.Various embodiments use an elicited cough to automatically determinetherapy levels. An accelerometer can be used to detect a vibration froma cough. Various embodiments of a remote cough vibration detectormonitor the output of the accelerometer after each neural stimulationpulse. If there is a signal on the accelerometer during or immediatelyfollowing neural stimulation pulse, then the detector can declare coughdue to the neural stimulation therapy. Various embodiments of the remotecough vibration detector monitor the output of the accelerometer duringthe initial portion of the neural stimulation burst to determine cough.Some embodiments confirm the presence of cough. For example, if cough isdetected two or more duty cycles in a row, then the presence of cough isconfirmed.

Some embodiments use cough vibration to rapidly titrate a neuralstimulation therapy. A cough vibration detector may be used toautomatically titrate therapy up or down based on whether there isvibration. This titration could be performed at the time of implant, atfollow-up visits to a clinical setting, or in an ambulatory patient. Invarious embodiments, rapid therapy titration is performed using acombination of inputs such as input from a cough vibration detector andinput from a laryngeal vibration detector. For example, laryngealvibration may be the marker for desired therapy but coughing isundesirable. In that case, therapy is titrated up to where a cough isdetected and then backed off and laryngeal vibration is then verified.Rapid therapy titration could be performed using a rate determinationsensor as well as a laryngeal vibration or cough detector.

Various embodiments provide physician-commanded titration, wheretitration is performed by the implanted device but under that manualinitiation of the physician, titration and physician monitoring of sideeffects may be performed by the physician where the physician manuallyprograms the therapy intensity (e.g. amplitude) up or down. Someembodiments provide a one-button initiation of titration and monitoringof side effects.

Various embodiments provide daily titration, where the titration oftherapy is performed automatically on a daily (or other periodic) basis.This allows the therapy intensity (e.g. amplitude) to be increased as apatient accommodates to the therapy. It may be desirable to drivetherapy to the greatest tolerable level if the increased in the therapyintensity provides a more effective therapy.

Various embodiments provide continuous monitoring, where the devicemonitors for laryngeal vibration and titrates up if detection is lost.The titration is initiated only by a triggering event, such as adetected cough, a loss in laryngeal vibration, and the like, rather thana daily titration or in addition to daily titration.

Various embodiments limit the neural stimulation system to an upperbound. In an embodiment, the intensity (e.g. amplitude) of the neuralstimulation is increased only to a maximum value because ofconsiderations such as safety, charge density limitations, longevity,and the like. For example, if the maximum value is reached beforelaryngeal vibration or cough is detected, the titration therapy would belimited to the maximum value.

Various embodiments limit the neural stimulation based on aclinician-supplied goal. For example, the physician may be provided witha programmable parameter for maximum amplitude. The physician may wantto program a maximum allowed therapy intensity (e.g. stimulationamplitude) that is lower than the system limit. The patient may notinitially be able to tolerate that value, but can as the patientaccommodates to the therapy. The system continues to attemptup-titrating at some period frequency until the physician supplied goalis met.

Various embodiments provide an offset from a cough threshold. Forexample, the offset can be a safety margin of one or two or more stepsdown from the level that elicit a cough. This could be a nominal or aprogrammable value to allow physician choice.

Various embodiments provide an offset from a laryngeal vibrationthreshold. For example, a safety margin of one or two or more steps up(or down) from the level that elicited laryngeal vibration. This couldbe a nominal or a programmable valued to allow physician choice. If aconflict arises between laryngeal vibration threshold plus offset, andcough threshold less offset, then an embodiment sets the level to thegreater of laryngeal vibration threshold plus offset or cough thresholdless offset. Other resolutions for the conflict may be implemented.

Various embodiments delay a scheduled titration, such as a dailytitration or a periodic titration, or a triggered titration. Titrationmay be delayed if the system detects that the patient is speaking.Titration during speaking may cause patient annoyance. Posture (patientstanding), activity, heart rate, arrhythmia detection may be used todetermine when to delay titration. Some embodiments provide a triggeredtitration down due to cough detection without delay, but allow titrationtriggered for other reasons to be delayed.

FIG. 32 illustrates an embodiment of a method for using an accelerometerto remotely sense respiratory parameter(s) for diagnostic purposes orfor a closed loop neural stimulation. At 3247, an accelerometer ismonitored to provide an acoustic signal. This acoustic signal from theaccelerometer may be filtered to provide an indicator of a heart soundas illustrated at 3248, to provide an indicator of neural stimulation asillustrated at 3249, and/or to provide an indicator of respiration asrepresented at 3250. At 3251, the signal indicative of respiration isprocessed. The heart sounds may be used in the signal processing toremove heart sound contributions from the signal. An ECG signal may alsobe used by a learning module to individualize the respiratory signal.The processed respiratory signal may be used to detect apnea asillustrated at 3252, to detect respiratory rate as illustrated at 3253,and to detect a respiratory event as illustrated at 3254. Apnea,respiration rate and/or respiration events may be used to providerespiration diagnostics 3255 or a closed loop neural stimulation therapy3256. Examples of respiration diagnostics includes estimated flow,average rate, apnea events, and the like.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the terms module and circuitry, for example, are intended to encompasssoftware implementations, hardware implementations, and software andhardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. In variousembodiments, the methods are implemented using a sequence ofinstructions which, when executed by one or more processors, cause theprocessor(s) to perform the respective method. In various embodiments,the methods are implemented as a set of instructions contained on acomputer-accessible medium such as a magnetic medium, an electronicmedium, or an optical medium.

The above detailed description is intended to be illustrative, and notrestrictive. Other embodiments will be apparent to those of skill in theart upon reading and understanding the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled.

What is claimed is:
 1. An implantable system configured to be implantedin a patient, comprising: an accelerometer; a neural stimulatorconfigured to deliver neural stimulation to a neural target; and acontroller configured to use the accelerometer to detect laryngealvibration, and configured to deliver a programmed neural stimulationtherapy using the neural stimulator and using detected laryngealvibration as an input to the programmed neural stimulation therapy,wherein the neural stimulator is configured to deliver the neuralstimulation at a neural stimulation frequency, the system furthercomprising a bandpass filter configured to filter an accelerometersignal to the neural stimulation frequency to detect laryngeal vibrationmodulated at the neural stimulation frequency, and wherein thecontroller is configured to use the accelerometer to detect cough, todeliver the neural stimulation with a programmed duty cycle including astimulation ON portion and a stimulation OFF portion, to monitor anaccelerometer signal for a cough during the ON portion, and to titratethe neural stimulation therapy if the cough occurs during the ON portionof the neural stimulation therapy.
 2. The system of claim 1, wherein thecontroller is configured to deliver the neural stimulation with aprogrammed duty cycle including a stimulation ON portion and astimulation OFF portion, to deliver a plurality of neural stimulationpulses during the stimulation ON portion, and to monitor a window oftime after a neural stimulation pulse for laryngeal vibration over athreshold.
 3. The system of claim 2, wherein the controller is furtherconfigured to monitor for laryngeal vibration after each neuralstimulation pulse during the stimulation ON portion, and to titrate theneural stimulation therapy if laryngeal vibration occurs more than athreshold number of times during the stimulation ON portion.
 4. Thesystem of claim 1, wherein the controller is configured to use theaccelerometer to detect cough, and to adjust an intensity of the neuralstimulation therapy to a level where laryngeal vibration is detected andcough is not detected.
 5. An implantable system configured to beimplanted in a patient, comprising: an accelerometer; a neuralstimulator configured to deliver neural stimulation to a neural target;and a controller configured to use the accelerometer to detect laryngealvibration or coughing, and configured to deliver a programmed neuralstimulation therapy using the neural stimulator and using detectedlaryngeal vibration or detected coughing as an input to the programmedneural stimulation therapy, wherein the controller is configured to usethe accelerometer to detect heart sounds and to use the detected heartsounds to provide an input to the neural stimulation therapy, whereinthe controller is configured to determine left ventricular ejection time(LVET) using the detected heart sounds and to use the LVET to provide aninput to the neural stimulation therapy.
 6. A method, comprising: usingan accelerometer to detect laryngeal vibration or coughing; andcontrolling a neural stimulation therapy using detected laryngealvibration as an input to the neural stimulation therapy, wherein theneural stimulation therapy is delivered with a neural stimulationfrequency, the method further comprising bandpass filtering anaccelerometer signal to the neural stimulation frequency to detectlaryngeal vibration modulated at the neural stimulation frequency,wherein the accelerator is used to detect cough, the neural stimulationtherapy is delivered with a programmed duty cycle, the programmed dutycycle including an ON portion and an OFF portion, and the neuralstimulation therapy delivers a plurality of neural stimulation pulsesduring the ON portion, the method further comprises monitoring anaccelerometer signal for a cough during the ON portion, and titratingthe neural stimulation therapy if the cough occurs during the ON portionof the neural stimulation therapy.
 7. The method of claim 6, wherein theneural stimulation therapy is delivered with a programmed duty cycle,the programmed duty cycle including a stimulation ON portion and astimulation OFF portion, and the neural stimulation therapy delivers aplurality of neural stimulation pulses during the stimulation ONportion, the method further comprises monitoring a window of time aftera neural stimulation pulse for laryngeal vibration over a threshold. 8.The method of claim 7, further comprising monitoring for laryngealvibration after each neural stimulation pulse, and titrating the neuralstimulation therapy if laryngeal vibration occurs more than a thresholdnumber of times during the stimulation ON portion.
 9. The method ofclaim 6, wherein the accelerometer is used to detect cough, andcontrolling the neural stimulation therapy includes adjusting anintensity of the neural stimulation therapy to a level where laryngealvibration is detected and cough is not detected.
 10. The method of claim6, wherein controlling the neural stimulation therapy includes:receiving a manual input from a clinician to initiate a titrationprocess; periodically initiating the titration process; or initiatingthe titration process in response to detecting a cough or laryngealvibration.
 11. The method of claim 6, wherein controlling the neuralstimulation therapy includes limiting an increase of neural stimulationintensity to an upper bound.
 12. The method of claim 6, whereincontrolling the neural stimulation using detected laryngeal vibration ordetected coughing includes offsetting an intensity of the neuralstimulation from a first threshold level at which laryngeal vibrationwas detected or a second threshold level at which coughing was detected.13. A method, comprising: using an accelerometer to detect laryngealvibration or coughing; controlling a neural stimulation therapy usingdetected laryngeal vibration or detected coughing as an input to theneural stimulation therapy; using the accelerometer to detect heartsounds; using the detected heart sounds to provide an input to theneural stimulation therapy; determining left ventricular ejection time(LVET) using the detected heart sounds; and using the LVET to provide aninput to the neural stimulation therapy.
 14. An implantable systemconfigured to be implanted in a patient, comprising: an accelerometer; aneural stimulator configured to deliver neural stimulation to a neuraltarget; and a controller configured to use the accelerometer to detectlaryngeal vibration, and configured to deliver a programmed neuralstimulation therapy using the neural stimulator and using detectedlaryngeal vibration as an input to the programmed neural stimulationtherapy, wherein the neural stimulator is configured to deliver theneural stimulation at a neural stimulation frequency, the system furthercomprising a bandpass filter configured to filter an accelerometersignal to the neural stimulation frequency to detect laryngeal vibrationmodulated at the neural stimulation frequency, wherein the controller isconfigured to use the accelerometer to detect cough, and to adjust anintensity of the neural stimulation therapy to a level where laryngealvibration is detected and cough is not detected.
 15. The system of claim14, wherein the controller is configured to deliver the neuralstimulation with a programmed duty cycle including a stimulation ONportion and a stimulation OFF portion, to deliver a plurality of neuralstimulation pulses during the stimulation ON portion, and to monitor awindow of time after a neural stimulation pulse for laryngeal vibrationover a threshold.
 16. The system of claim 15, wherein the controller isfurther configured to monitor for laryngeal vibration after each neuralstimulation pulse during the stimulation ON portion, and to titrate theneural stimulation therapy if laryngeal vibration occurs more than athreshold number of times during the stimulation ON portion.
 17. Amethod, comprising: using an accelerometer to detect laryngeal vibrationor coughing; and controlling a neural stimulation therapy using detectedlaryngeal vibration as an input to the neural stimulation therapy,wherein the neural stimulation therapy is delivered with a neuralstimulation frequency, the method further comprising bandpass filteringan accelerometer signal to the neural stimulation frequency to detectlaryngeal vibration modulated at the neural stimulation frequency,wherein the accelerometer is used to detect cough, and controlling theneural stimulation therapy includes adjusting an intensity of the neuralstimulation therapy to a level where laryngeal vibration is detected andcough is not detected.
 18. The method of claim 17, wherein the neuralstimulation therapy is delivered with a programmed duty cycle, theprogrammed duty cycle including a stimulation ON portion and astimulation OFF portion, and the neural stimulation therapy delivers aplurality of neural stimulation pulses during the stimulation ONportion, the method further comprises monitoring a window of time aftera neural stimulation pulse for laryngeal vibration over a threshold. 19.The method of claim 18, further comprising monitoring for laryngealvibration after each neural stimulation pulse, and titrating the neuralstimulation therapy if laryngeal vibration occurs more than a thresholdnumber of times during the stimulation ON portion.
 20. The method ofclaim 17, wherein controlling the neural stimulation therapy includes:receiving a manual input from a clinician to initiate a titrationprocess; periodically initiating the titration process; or initiatingthe titration process in response to detecting a cough or laryngealvibration.
 21. The method of claim 17, wherein controlling the neuralstimulation therapy includes limiting an increase of neural stimulationintensity to an upper bound.
 22. The method of claim 17, whereincontrolling the neural stimulation using detected laryngeal vibration ordetected coughing includes offsetting an intensity of the neuralstimulation from a first threshold level at which laryngeal vibrationwas detected or a second threshold level at which coughing was detected.23. A method, comprising: using an accelerometer to detect laryngealvibration or coughing; and controlling a neural stimulation therapyusing detected laryngeal vibration as an input to the neural stimulationtherapy, wherein the neural stimulation therapy is delivered with aneural stimulation frequency, the method further comprising bandpassfiltering an accelerometer signal to the neural stimulation frequency todetect laryngeal vibration modulated at the neural stimulationfrequency, wherein controlling the neural stimulation using detectedlaryngeal vibration or detected coughing includes offsetting anintensity of the neural stimulation from a first threshold level atwhich laryngeal vibration was detected or a second threshold level atwhich coughing was detected.
 24. The method of claim 23, wherein theneural stimulation therapy is delivered with a programmed duty cycle,the programmed duty cycle including a stimulation ON portion and astimulation OFF portion, and the neural stimulation therapy delivers aplurality of neural stimulation pulses during the stimulation ONportion, the method further comprises monitoring a window of time aftera neural stimulation pulse for laryngeal vibration over a threshold. 25.The method of claim 23, further comprising monitoring for laryngealvibration after each neural stimulation pulse, and titrating the neuralstimulation therapy if laryngeal vibration occurs more than a thresholdnumber of times during the stimulation ON portion.
 26. The method ofclaim 23, wherein controlling the neural stimulation therapy includes:receiving a manual input from a clinician to initiate a titrationprocess; periodically initiating the titration process; or initiatingthe titration process in response to detecting a cough or laryngealvibration.
 27. The method of claim 23, wherein controlling the neuralstimulation therapy includes limiting an increase of neural stimulationintensity to an upper bound.